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The high-frequency major histocompatibility complex class I allele Mamu-B*17 is associated with control of simian immunodeficiency virus SIVmac239 replication.

Particular HLA alleles are associated with reduced human immunodeficiency virus replication. It has been difficult, however, to characterize the immune correlates of viral control. An analysis of the influence of major histocompatibility complex class I alleles on viral control in 181 simian immunodeficiency virus SIVmac239-infected rhesus macaques revealed that Mamu-B(*)17 was associated with a 26-fold reduction in plasma virus concentrations (P<0.001). Mamu-B(*)17 was also enriched in a group of animals that controlled viral replication by 1,000-fold [corrected] Even after accounting for this group, Mamu-B(*)17 was associated with an eightfold reduction in plasma virus concentrations (P<0.001). Mamu-B(*)17-positive macaques could, therefore, facilitate our understanding of the correlates of viral control.

Alleles↗

Vaccine strategies for infectious diseases.

Infectious diseases are the major cause of death worldwide; in developing countries such diseases are responsible for nearly half the burden of premature death and disability. Therefore, the need for the development of new vaccine strategies aimed at preventing or limiting disease is extremely urgent. Important successes have been achieved against some infectious diseases that were once endemic or, even, epidemic (e.g., polio, smallpox, diptheria). Advances in our knowledge of the pathogenesis and immune correlates of protections are needed to develop novel vaccinal approaches to diseases such as hepatitis C, AIDS and malaria. In this review we will analyse the biological problems associated with the prevention of development and/or improvement of vaccine strategies for infectious diseases, focusing on the difficulties facing the creation of new effective vaccines for HIV infection and malaria.

Journal Article↗

Design of multi-epitope, analogue-based cancer vaccines.

The current objective of our cancer programme is to develop an effective vaccine based on rationally designed T cell epitope analogues, for use in the adjuvant setting for non-small cell lung cancer (NSCLC) and colon cancer. Analogue epitopes, enhanced for either human leukocyte antigen (HLA) binding or T cell receptor (TCR) signalling, have been shown to be more effective at breaking immunological tolerance than cognate wild-type epitopes. Although encouraging early-phase clinical data has been obtained by others using a limited number of HLA-A2-restricted epitope analogues, the clinical benefits and immune correlates for vaccines comprised of multiple epitope analogues restricted by multiple HLA supertypes remains to be investigated. Clinical studies are currently being conducted on EP-2101, a prototype vaccine that delivers multiple HLA-A2-restricted analogue epitopes. In parallel, fixed anchor and heteroclitic analogues restricted by three other commonly expressed HLA supertypes are being identified. These analogues will be incorporated into future vaccines including optimised minigenes (epigenes) and tested in preclinical and clinical studies addressing various different cancer indications.

Animals↗

Transmission and immunopathogenesis of FIV in cats as a model for HIV.

The feline immunodeficiency virus (FIV) model provides a system to study lentivirus transmission, virus kinetics, pathogenesis, host responses, and immune dysfunction in a natural, out-bred host, under controlled conditions with specific-pathogen-free animals. The diversity of primary FIV strains can be exploited to mirror the range of disease manifestations associated with HIV infection. FIV is infectious via intravenous, intraperitoneal, intradermal, or subcutaneous injection as well as by atraumatic instillation onto the oral, vaginal, or rectal mucosa. Together, these features allow investigators to model specific aspects of HIV infection in a highly relevant and relatively inexpensive animal model. Well-developed areas of the FIV model include: (1) transmission of cell-associated as well as cell-free virus; (2) mucosal infectivity and immunopathogenesis; (3) vertical transmission; (4) acquired immunodeficiency including defects of the innate immune system; (5) thymic dysfunction; (6) neurotropism and neuropathogenesis; (7) host-virus interactions and the role of specific gene products; (8) efficacy of antiviral therapy; and (9) efficacy and immune correlates of experimental vaccines. This review will encompass areas specific to transmission and immunopathogenesis.

Animals↗

Antibody response to pneumococcal polysaccharides in insulin-dependent diabetes mellitus.

Twenty-one insulin-dependent diabetics and 11 healthy control children were immunized with polyvalent pneumococcal polysaccharide vaccine. Serum antibody to pneumococcal polysaccharides was measured by radioimmunoassay before and after immunization. Although there were some differences in type-specific antibody concentrations between diabetic and control subjects, the overall antibody concentrations preimmunization, 3-4 wk postimmunization, and 6-7 wk postimmunization were similar in both populations. In both groups antibody response to immunization correlated strongly with preimmunization antibody concentration. Among the diabetic subjects there was no correlation between antibody responses and duration of disease, insulin dose, or concentration of glycosylated hemoglobin. Insulin-dependent diabetic subjects have a serum antibody response to pneumococcal polysaccharides equivalent to that of controls, and in both populations the magnitude of the antibody response correlates with preimmunization antibody levels.

Adolescent↗

Protective antigens and mechanisms of anti-Candida immunity.

Life threatening fungal diseases are now frequent in a substantial fraction of the immunocompromised host population. The toxicity and the relative scarcity of efficacious antifungal drugs highlight the need for developing alternative or integrative immunoprophylactic and therapeutic tools; among them the need to develop prophylactic or therapeutic vaccines against candidiasis, a widespread mucosal or deep-seated infection caused primarily by the fungus Candida albicans, are of clear priority. Vaccination is a highly beneficial medical practice, and probably the most cost-effective measure against disease onset and progression. It is based on the use of microbial antigens capable of conferring protection in a susceptible target host. To date, only a handful of Candida albicans antigens have been produced and very few of them have been thoroughly investigated for immunogenicity and protection in experimental models of candidiasis. Thus, approaches to the molecular, biochemical and functional characterization of novel C. albicans encoded molecules are most welcome to improve the perspective of developing in the near future an effective vaccine against C. albicans. Identification of anti-Candida vaccine candidates must take into account the diversity of Candida diseases, the various underlying mechanisms of protection as well as the major immune dysfunctions observed as predisposing factors for disease. Antigens to be considered possible vaccine candidates include members of the aspartyl proteinase (Sap2) family and the 65kDa mannoprotein (MP65) antigen. An additional molecule of C. albicans which has not yet been identified but deserves great consideration as a vaccine candidate is the yeast-killer toxin receptor (KTR). Initial experimental evidence strongly suggests that the above antigens are able to elicit protective immunity against mucosal and/or systemic candidiasis. A series of molecular, biochemical and immunological studies aimed at validating and strengthening this initial evidence are in progress, with the ultimate goal of producing recombinant or natural antigens that can be assessed for their ability to elicit a protective immunity in animal models and the mechanisms whereby protection is achieved, with emphasis on determination of immune correlates of protection.

Animals↗

Molecular and functional characterization of NKG2D, NKp80, and NKG2C triggering NK cell receptors in rhesus and cynomolgus macaques: monitoring of NK cell function during simian HIV infection.

An involvement of innate immunity and of NK cells during the priming of adaptive immune responses has been recently suggested in normal and disease conditions such as HIV infection and acute myelogenous leukemia. The analysis of NK cell-triggering receptor expression has been so far restricted to only NKp46 and NKp30 in Macaca fascicularis. In this study, we extended the molecular and functional characterization to the various NK cell-triggering receptors using PBMC and to the in vitro-derived NK cell populations by cytofluorometry and by cytolytic activity assays. In addition, RT-PCR strategy, cDNA cloning/sequencing, and transient transfections were used to identify and characterize NKp80, NKG2D, CD94/NKG2C, and CD94/NKG2A in M. fascicularis and Macaca mulatta as well as in the signal transducing polypeptide DNAX-activating protein DAP-10. Both M. fascicularis and M. mulatta NK cells express NKp80, NKG2D, and NKG2C molecules, which displayed a high degree of sequence homology with their human counterpart. Analysis of NK cells in simian HIV-infected M. fascicularis revealed reduced surface expression of selected NK cell-triggering receptors associated with a decreased NK cell function only in some animals. Overall surface density of NK cell-triggering receptors on peripheral blood cells and their triggering function on NK cell populations derived in vitro was not decreased compared with uninfected animals. Thus, triggering NK cell receptor monitoring on macaque NK cells is possible and could provide a valuable tool for assessing NK cell function during experimental infections and for exploring possible differences in immune correlates of protection in humans compared with cynomolgus and rhesus macaques undergoing different vaccination strategies.

Amino Acid Sequence↗

HIV-specific CD8+ lymphocytes in semen are not associated with reduced HIV shedding.

Sexual contact with HIV-infected semen is a major driving force behind the global HIV pandemic. Little is known regarding the immune correlates of virus shedding in this compartment, although HIV-1-specific CD8+ T cells are present in semen. We collected blood and semen from 27 chronically HIV-infected, therapy-naive men without common sexually transmitted infections or urethral inflammation and measured HIV-1 RNA viral load and cytokine/chemokine levels in both compartments. HIV-1 RNA levels were 10-fold higher in blood than semen, but discordantly high semen shedding was associated with higher semen levels of the proinflammatory cytokines IL-6, IL-8, IL-12, and IFN-gamma. Virus-specific CD8+ T cell epitopes were mapped in blood by IFN-gamma ELISPOT, using an overlapping HIV-1 clade B peptide matrix, and blood and semen CD8+ T cell responses were then assayed ex vivo using intracellular IFN-gamma staining. HIV-specific CD8+ responses were detected in 70% of semen samples, and their frequency was similar to or higher than blood. There was no correlation between the presence of virus-specific CD8+ T cells in semen and levels of HIV-1 RNA shedding. Among participants with detectable CD8+ IFN-gamma semen responses, their relative frequency was not associated with reduced HIV-1 RNA shedding, and their absolute number was correlated with higher levels of HIV-1 RNA semen shedding (r = 0.6; p = 0.03) and of several proinflammatory cytokines. Neither the presence nor the frequency of semen HIV-specific CD8+ T cell IFN-gamma responses in semen correlated with reduced levels of HIV RNA in semen.

CD8-Positive T-Lymphocytes↗

[Pharmacokinetic properties of pancreatic and microbial ribonucleases].

Pharmacokinetic properties of pancreatic RNAase (RNAase I), RNAase of Bacillus intermedius (RNAase Bi) and RNAase of Streptomyces rimosus (RNAase Sr) were studied on albino rats. RNAase Bi was shown to be characterized by a higher rate and level of absorption into the systemic blood flow, higher retention time, lower elimination from the kidneys and tissues of the peripheral chamber (skeletal muscles) and higher distribution in the other animal organs such as the heart, spleen and brain. It was concluded by the experimental results that the higher antiviral efficacy of RNAase Bi (RNAase Bi greater than RNAase Sr greater than RNAase I), as was known from the literature data, and the ability to stimulate the immunity correlated with higher biological availability of the enzyme in the animals and could be due to its pharmacokinetic properties.

Animals↗

[Immunological characteristics of viral myocarditis].

A study of cellular and humoral immunity was conducted in patients with viral myocarditis. Quantitative and functional deficiency of T-suppressors and an increase in the number of cytotoxic lymphocytes were revealed in most patients. Disorder in the T-cellular link of immunity correlated with a clinical course of the disease and was found more frequently in patients with a grave course of myocarditis.

Adolescent↗

Identification of a surface antigen on Loa loa microfilariae the recognition of which correlates with the amicrofilaremic state in man.

Filarial infections induce a spectrum of disease in their natural hosts, and by correlating immunity found in individuals with their disease pattern, one may delineate non-pathogenic, protective mechanisms. Loa loa is causal of mild to moderate pathology, and it is unique among the human filaria in that adult worms are occasionally visible during subconjunctival migration. To study immune mechanisms controlling microfilaremia, sera from 15 subjects with amicrofilaremic occult loiasis (OL) were compared with sera from 10 subjects with microfilaremic loiasis (ML) microfilaremia, (greater than 4000/ml) for their reactions with living microfilariae (mf). An IFA was first used to detect antibodies able to bind to the surface of living L. loa mf. ML subjects either did not react (7/10) or reacted only very weakly (3/10). Highly reactive sera were found only in OL subjects; 7/15 gave very bright fluorescence, 5/15 gave moderate reactions, and 3/15 were negative. Most of these antibodies were of the IgG class. Sera from all subjects were also reacted with living mf in an antibody-dependent cellular adherence test using normal leukocytes. Sera that were strongly positive in IFA showed strong adherence and IFA-negative sera were non-reactive. To identify the Ag involved, mf were surface iodinated, detergent-extracted Ag were immunoprecipitated, and Mr was determined on SDS-PAGE. Several OL sera, all highly reactive in the above tests, precipitated a 23-kDa molecule with which all ML sea failed to react. Sera from a mandrill experimentally infected with L. loa also precipitated the 23-kDa Ag when taken post-patency. In conclusion, it appears that certain people who control L. loa microfilaremia have high levels of IgG antibodies that bind to a surface Ag of 23 kDa and are able to mediate cellular adherence.

Adhesiveness↗

Comparison of radioimmunoassay and indirect hemagglutination for quantitation of antipneumococcal antibodies.

The RIA and IHA methods to quantitate antipneumococcal antibodies of six capsular types (3, 6A, 8, 12F, 14, and 18C) were compared in 30 paired sera 1 month after pneumococcal immunization. Correlation coefficients for titers were significantly different from zero (p less than 0.001) for all types except 14 and ranged from 0.86 for type 3 to 0.45 for type 18C. In sera that showed a twofold or greater rise by RIA, 50% to 83% showed a fourfold or greater rise by IHA, depending on the capsular type. Conversely, in those sera showing an IHA rise of fourfold or more, 79% to 100% showed an RIA rise of twofold or more. IHA titers correlating with RIA titers greater than or equal to 200 ng AbN/ml varied from 1:16 for type 18C to 1:64 for types 3, 8, and 12F.

ABO Blood-Group System↗

Immune responses and chronic lymphedema in experimental filariasis.

Chronic lymphedema is a clinically important manifestation of lymphatic filariasis but the factors which govern the development and progression of lymphedema remain unclear. Because immune responses are major determinants of disease expression in filariasis, we compared immune responses in ferrets reinfected with B. malayi in which disease expression varied from virtually no overt disease to severe chronic lymphedema of the infected limbs. No immune correlates specific for development of chronic lymphedema were identified by antigen recognition profiles (Western-blots), magnitude of the antibody (IgG) responses (ELISA) or blastogenic responses of lymphocytes to filarial extracts. Prausnitz-Kustner (PK) tests for filarial specific IgE indicated that the initial period of a severe lymphedema, which became chronic, often was associated with relatively high IgE titers. The results suggest that a high level of immediate hypersensitivity to filarial antigens is a significant factor in initiating persistent lymphedema on reinfections of partially resistant hosts. Histologic study of persistent edema of up to 2 years duration demonstrated dermal changes consistent with chronic lymphedema, but not the dermal proliferation characteristic of elephantiasis.

Animals↗

[Delayed local reaction (DLR) after BCG vaccination in mice. II.--Correlations with the immune response (author's transl)].

The occurrence and intensity of the DLR were correlated with different parameters of the specific and non-specific immune response induced by the inoculation of viable BCG into the footpad. A good parallel exists between the occurrence of the DRL and effector mechanisms which tend to limit the growth of BCG in the draining node, and also with the appearance of tuberculin hypersensitivity measured in vivo by skin-test. Nonspecific immunity induced in mice after subcutaneous BCG injection was measured using the relative spleen weight, and this correlates well with the onset of the DLR. Delayed type hypersensitivity (DTH) to varying doses of sheep red blood cells (SRBC) injected intravenously in normal or in subcutaneously BCG-pretreated mice indicated a functional increase of the reticuloendothelial system activity, 14 days after BCG injection. Lastly, the degree of adjuvanticity induced by BCG vaccination to DTH against SRBC which were injected in the same footpad, was strictly correlated with the kinetics of the DLR. The value of measuring DLR in mice is discussed concerning the evaluation of the immunogenicity of BCG vaccines and slso the host's capability to mount an immune response after subcutaneous BCG injection.

Adjuvants, Immunologic↗

Adaptation to chronic stress. Temporal pattern of immune and neuroendocrine correlates.

Stress-inducing stimuli are associated with a suppression of immune function. In this study, the relationship between pituitary-adrenal hormone release and natural cytoxicity was examined in the rat during single and repeated instances of chronic stress. Increased plasma concentrations of both adrenocorticotropic hormone (ACTH) and beta-endorphin/lipotropin were correlated with increases in natural killer (NK) activity following a single period of immobilization. After 4 days of repeated daily immobilization (2.5 hours/day), the secretory response of beta-endorphin/lipotropin was similar to that on day 1, but NK activity was lower than on day 1. These observations suggest a complex interaction between pituitary-adrenal responses to stress and changes in natural cytoxicity.

Adrenocorticotropic Hormone↗

Clinical correlates of circulating immune complexes and antibody reactivity in squamous cell carcinoma of the head and neck. The Department of Veterans Affairs Laryngeal Cancer Study Group.

PURPOSE: To evaluate the correlation between the presence and titer of host-derived antibody reactivity, circulating immune complexes, and clinical course and prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Serum samples, obtained from untreated patients with squamous cell carcinoma of the larynx entered onto a multiinstitutional trial, were evaluated for the presence of elevated circulating immune complexes (221 patients) and host-derived antibody directed against two SCCHN cell lines (107 patients). RESULTS: Patients had significantly elevated levels of circulating immune complexes as measured by C1q binding compared with normal controls. Patients with higher levels of circulating immune complexes were less likely to respond to chemotherapy. No correlations were noted between immune complex levels and stage of disease, nodal status, site of disease, recurrence, or survival. Evaluation of native antibody titers for their relationship to clinical correlates showed no statistically significant associations. In sera subjected to immune complex dissociation, patients with moderately or poorly differentiated tumors had significantly higher antibody titers when compared with patients with well-differentiated tumors. Because marked variation in the increase of antibody titers following immune complex dissociation was noted, the ratio of immune complex-dissociated to native antibody titer was examined. Patients with a high ratio had a lower proportion of complete and partial responses to chemotherapy. CONCLUSION: Our results support the conclusion that the formation of tumor-associated immune complexes in patients with SCCHN is associated with a decreased response to chemotherapy.

Antibodies, Neoplasm↗

Missed opportunities to immunize: psychosocial and practice correlates.

BACKGROUND: The goal of this pilot study was to correlate missed opportunities to immunize young children with providers' psychosocial characteristics and self-reported immunization practices. METHODS: In a population of children aged 0 to 36 months, missed opportunities to immunize were established for a sample of 28 providers, who also responded to a valid and reliable instrument measuring the aforementioned variables. RESULTS: Missed opportunities were significantly lower among providers with higher vested interest (r=-0.45, p=0.02) and tended to be lower among providers with more positive attitudes toward having all children properly immunized at every healthcare visit (r=-0.33, p =0.09). Neither knowledge nor perceived barriers correlated significantly with missed opportunities. Providers missed opportunities to immunize in over half of the visits studied (mean, 0.58), yet all of them reported always immunizing at preventive and follow-up visits, almost all (96.3%) at chronic illness visits, and a majority (78.6%) at acute care visits. As a result, none of the self-reported immunization practices was significantly correlated with missed opportunities. CONCLUSIONS: Missed opportunities appear to be best predicted by motivational psychosocial factors and not by knowledge or perceived barriers. Self-reported immunization practices do not correspond to actual immunization behavior.

Child, Preschool↗

Correlation between specific immunity to a metabolite of halothane and hepatic lesions after multiple exposures.

A correlation between the use of halogenated anesthetic agents and liver necrosis is not yet established in man. In an attempt to resolve this dilemma, guinea pigs were immunized with a complex of guinea-pig albumin and trifluoroacetate (TFA), a common metabolite of halothane and fluorexene, and then exposed to halothane on multiple occasions. Histology and liver-function tests showed no difference in the incidence of liver damage between groups of animals immune to TFA with cellular immunity and untreated control animals. However, a difference in the liver enzyme levels was seen between controls and animals showing humoral immunity.

Animals↗